Clopixol depot

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLOPIXOL DEPOT (CLOPIXOL® DEPOT)

Composition:

Active substance: zuclopenthixol;

1 ml of solution contains zuclopenthixol decanoate 200 mg;

Excipients: medium-chain triglycerides.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, yellowish oily solution, practically free from mechanical particles.

Pharmacotherapeutic group. Psycholeptics. Antipsychotics. Thioxanthene derivatives. Zuclopenthixol.

ATC code N05AF05.

Pharmacological properties.

Pharmacodynamics.

Zuclopenthixol is a neuroleptic agent belonging to the thioxanthene group.

The antipsychotic effect of neuroleptics is associated with blockade of dopamine receptors, as well as possible involvement of 5-HT receptor blockade. In vitro, zuclopenthixol has high affinity for both dopamine D1 and D2 receptors, α1-adrenergic receptors, and 5-HT2 receptors (5-hydroxytryptamine), but lacks affinity for cholinergic muscarinic receptors. It has weak affinity for histamine (H1) receptors and does not exert blocking effects on α2-adrenergic receptors.

In vivo, affinity for D2 binding sites predominates over affinity for D1 receptors. Zuclopenthixol is a high-potency neuroleptic, as demonstrated by all behavioral tests of neuroleptic activity (ability to block dopamine receptors). At average daily oral dosing for antipsychotic treatment, affinity for blocking sites binding the dopaminergic D2 receptor has been observed in both in vitro and in vivo models.

Like most other neuroleptics, zuclopenthixol increases serum prolactin levels.

Pharmacological studies have clearly demonstrated that the oily solution of zuclopenthixol decanoate exerts a prolonged neuroleptic effect, and the amount of drug required to maintain a constant effect over a prolonged period is significantly lower with the depot formulation than with daily oral administration of zuclopenthixol. From a clinical standpoint, these pharmacological data suggest that a sustained neuroleptic effect without marked sedation can be achieved using the depot formulation. Moreover, a low risk of interaction with anesthetics can be expected.

Clinical efficacy and safety

In clinical practice, zuclopenthixol decanoate is indicated for maintenance treatment of patients with chronic psychotic disorders. Positive results have also been obtained in the treatment of hyperactive and aggressive patients with intellectual disability.

The specific inhibitory action of zuclopenthixol decanoate justifies its use in treating psychotic patients with symptoms of agitation, restlessness, hostility, and aggression.

Zuclopenthixol decanoate produces a transient, dose-dependent sedative effect. However, if a patient switches from oral zuclopenthixol or from zuclopenthixol acetate injections to maintenance therapy with zuclopenthixol decanoate, the risk of sedation is reduced. Tolerance to the non-specific sedative effect develops rapidly.

Zuclopenthixol decanoate is particularly effective in treating agitated, restless, hostile, or aggressively disposed patients.

Zuclopenthixol decanoate enables continuous treatment, which is extremely important for patients who are non-compliant with physician-prescribed oral zuclopenthixol regimens. Zuclopenthixol decanoate prevents frequent relapses associated with patient interruption of oral antipsychotic therapy.

Pharmacokinetics.

Absorption

By esterifying zuclopenthixol with decanoic acid, zuclopenthixol is converted into a highly lipophilic substance—zuclopenthixol decanoate. When dissolved in oil and administered intramuscularly, the ester diffuses slowly from the oil into the body's aqueous phase, after which it is rapidly hydrolyzed, releasing the active zuclopenthixol.

Maximum serum concentration is reached 3–7 days after injection.

The elimination half-life after intramuscular injection is 3 weeks (reflecting release from the depot). Steady-state concentrations are achieved with repeated administration over 3 months.

Distribution

The apparent volume of distribution (Vd) β is approximately 20 L/kg.

Plasma protein binding is approximately 98–99%.

Biological transformation

Zuclopenthixol is metabolized via three main pathways: sulfoxidation, N-dealkylation of the side chain, and conjugation with glucuronic acid. Metabolites lack psychopharmacological activity. The pharmacological effect of unchanged zuclopenthixol predominates over the effects of its metabolites in the brain and other tissues, as zuclopenthixol metabolites lack neuroleptic activity.

Excretion

The elimination half-life (t1/2β) of zuclopenthixol is approximately 20 hours; systemic clearance (Cls) is approximately 0.86 L/min.

Metabolites are devoid of neuroleptic activity and are excreted mainly in feces and partially in urine (10%).

Only about 0.1% of the dose is excreted unchanged in urine, indicating minimal renal drug load.

The mean ratio of active substance concentration in human breast milk to active substance concentration in serum in women was approximately 0.29 just before the next dose during steady-state maintenance therapy with oral or intramuscular zuclopenthixol decanoate.

Linearity

Kinetics are linear. With administration of 200 mg zuclopenthixol decanoate every 2 weeks, the mean trough steady-state level was approximately 10 ng/mL (25 nmol/L).

Elderly patients

Pharmacokinetic parameters are significantly dependent on patient age.

Renal impairment

Given the excretion characteristics described above, it can be assumed that reduced renal function is unlikely to have a major impact on serum drug levels.

Hepatic impairment

No data available.

Polymorphism

In vivo studies have shown that some metabolic pathways are subject to genetic polymorphism of sparteine/debrisoquine oxidation (CYP2D6).

Pharmacokinetic/pharmacodynamic interactions

Serum (plasma) concentration prior to the next injection in the range of 2.8–12 ng/mL (7–30 nmol/L), with maximum-to-minimum fluctuation less than 2.5, is recommended for maintenance treatment of patients with moderate severity schizophrenia.

Pharmacokinetically, a dose of 200 mg zuclopenthixol decanoate every 2 weeks or 400 mg every 4 weeks is equivalent to a daily oral dose of 25 mg of Clopixol.

Clinical characteristics.

Indications.

Maintenance therapy of schizophrenia and other psychoses, particularly those with symptoms such as hallucinations, mania, and thought disorders associated with excitement, agitation, hostility, and aggression.

Contraindications.

Hypersensitivity to any component of the drug. Circulatory collapse, impaired consciousness of any origin (e.g., due to alcohol, barbiturate, or opioid intoxication), coma.

Interaction with other medicinal products and other forms of interaction.

Combinations requiring caution during use

Zuclopenthixol decanoate may enhance the sedative effects of alcohol, barbiturates, and central nervous system inhibitors.

Neuroleptics may potentiate or reduce the effects of antihypertensive agents; the hypotensive effect of guanethidine and similarly acting drugs is diminished.

Zuclopenthixol may potentiate the effects of general anesthetics and anticoagulants and prolong the duration of action of neuromuscular blocking agents.

Anticholinergic effects of atropine or other medicinal products with anticholinergic properties may be enhanced.

Concomitant use of neuroleptics, lithium, or sibutramine increases the risk of neurotoxicity.

Tricyclic antidepressants and neuroleptics mutually inhibit each other's metabolism, and glycemic control in diabetes may be impaired.

Zuclopenthixol decanoate may reduce the efficacy of levodopa, adrenergic agents, and anticonvulsants; combinations with metoclopramide, piperazine, and antiparkinsonian drugs increase the risk of extrapyramidal disorders such as tardive dyskinesia.

Antipsychotics may enhance the cardiodepressant effects of quinidine and affect the absorption of corticosteroids and digoxin.

The hypotensive effect of vasodilator antihypertensive agents such as hydralazine, α-blockers (e.g., doxazosin), or methyldopa may be enhanced.

Concomitant use of zuclopenthixol and medicinal products known to prolong the QT interval or induce cardiac arrhythmias—such as tricyclic antidepressants or other antipsychotics—should be avoided.

Since zuclopenthixol is partially metabolized by CYP2D6, concomitant use of drugs capable of inhibiting this enzyme may reduce zuclopenthixol elimination.

QT interval prolongation associated with antipsychotic use may be exacerbated when combined with other agents capable of significantly prolonging the QT interval. Combinations with the following medicinal products should be avoided:

• Class Ia and III antiarrhythmics (e.g., quinidine, amiodarone, sotalol, dofetilide).
• Certain antipsychotics (e.g., thioridazine).
• Certain macrolide antibiotics (e.g., erythromycin).
• Certain antihistamines (e.g., terfenadine, astemizole).
• Certain quinolone antibiotics (e.g., gatifloxacin, moxifloxacin).

The above list is incomplete. Combinations with other individual drugs known to significantly prolong the QT interval (such as cisapride, lithium) should also be avoided.

Agents that alter electrolyte balance, such as thiazide diuretics (causing hypokalemia), and agents that increase zuclopenthixol concentrations should also be used with caution, as they may increase the risk of QT interval prolongation and life-threatening arrhythmias.

Antipsychotics may exhibit antagonism to the effects of adrenaline and other sympathomimetics and may neutralize the antihypertensive effects of guanethidine and similar adrenergic-blocking agents.

Special precautions for use.

Caution is required in patients with the following conditions: liver disease; heart disease or arrhythmias; severe respiratory disorders; renal insufficiency; epilepsy (and conditions predisposing to epilepsy, such as alcohol withdrawal or brain injury); Parkinson's disease; narrow-angle glaucoma; prostate hypertrophy; hypothyroidism; hyperthyroidism; myasthenia gravis; pheochromocytoma; and patients with known hypersensitivity to thioxanthenes or other antipsychotics.

Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia, have been reported following abrupt discontinuation of antipsychotics. Additionally, relapses of psychotic symptoms may occur, and cases of involuntary movement disorders (such as akathisia, dystonia, and dyskinesia) have been reported.

Plasma concentrations of zuclopenthixol decanoate gradually decrease over several weeks, making a gradual tapering with stepwise dose reduction unnecessary.

When switching patients from oral antipsychotics to depot antipsychotics, the oral medication should not be discontinued abruptly; it should be tapered gradually over several days after the first depot injection.

There is a risk of developing neuroleptic malignant syndrome (hyperthermia, muscle rigidity, altered consciousness, autonomic dysfunction) with any antipsychotic. The risk may be higher when multiple agents are used. Fatal cases predominantly occur in patients with pre-existing organic brain syndrome, mental retardation, or opioid and alcohol abuse.

Treatment: discontinue antipsychotics, provide symptomatic and general supportive care. Dantrolene and bromocriptine may be used.

Symptoms may persist for one week or longer after discontinuation of oral formulations and somewhat longer after administration of depot formulations.

Like other antipsychotics, zuclopenthixol decanoate should be used cautiously in patients with organic brain syndrome, seizures, and progressive liver disease.

Rare cases of pathological changes in blood parameters have been reported. If a patient develops signs of persistent infection, complete blood counts should be performed.

Like other antipsychotics, zuclopenthixol decanoate may alter insulin requirements and glucose tolerance, necessitating adjustments in antidiabetic therapy in diabetic patients.

During maintenance therapy, especially with high doses, patients should be closely monitored, and the possibility of reducing the maintenance dose should be periodically evaluated.

Like other agents in the antipsychotic therapeutic class, zuclopenthixol decanoate may prolong the QT interval. Pre-existing QT prolongation may increase the risk of life-threatening arrhythmias. Therefore, zuclopenthixol decanoate should be used with caution in patients with suspected hypokalemia, hypomagnesemia, or genetic predisposition to such conditions, as well as in patients with a history of cardiovascular disease, such as prolonged QT interval, marked bradycardia (<50 bpm), recent myocardial infarction, decompensated heart failure, or cardiac arrhythmia. Concomitant use with other antipsychotics should be avoided.

Cases of venous thromboembolism (VTE) have been reported during antipsychotic therapy. Since patients receiving antipsychotics often have acquired VTE risk factors, all potential VTE risk factors should be identified before and during treatment with zuclopenthixol decanoate, and preventive measures should be taken.

Elderly patients

Elderly patients require careful monitoring, as they are particularly susceptible to adverse effects such as sedation, arterial hypotension, confusion, and disturbances in body temperature regulation.

Cerebrovascular events

In randomized, placebo-controlled trials of some atypical antipsychotics in patients with dementia, the risk of cerebrovascular adverse events was approximately three times higher. The mechanism of this increased risk is unknown. An increased risk cannot be excluded for other antipsychotics or other patient populations. Zuclopenthixol decanoate should be used with caution in patients with risk factors for stroke.

Increased mortality in elderly patients with dementia

Clinical trial data indicate that elderly patients with dementia treated with antipsychotics have a slightly higher risk of death compared to those not receiving these drugs. Data are insufficient to precisely quantify this risk, and the cause of the increased risk is unknown.

Zuclopenthixol decanoate is not indicated for the treatment of behavioral disorders associated with dementia.

Cases of leukopenia, neutropenia, and agranulocytosis have been reported with antipsychotics, including zuclopenthixol decanoate. Long-acting depot antipsychotics should be used cautiously in combination with other agents with myelosuppressive potential, as these formulations cannot be rapidly eliminated from the body if necessary.

Use during pregnancy or breastfeeding.

Pregnancy

Zuclopenthixol decanoate should not be administered during pregnancy unless the expected benefit to the patient outweighs the theoretical risk to the fetus.

Newborns whose mothers have taken antipsychotics (including zuclopenthixol decanoate) during the third trimester of pregnancy may be at risk of developing adverse effects, including extrapyramidal symptoms or withdrawal symptoms, which may vary in severity and duration after delivery. Cases of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding difficulties have been reported. Therefore, newborns require careful monitoring.

Animal studies have shown reproductive toxicity.

Breastfeeding

The drug is excreted in breast milk in low concentrations, and its effect on the infant at therapeutic doses is unlikely. The dose received by the infant through breast milk is less than 1% of the mother's daily dose and depends on the mother's body weight (mg/kg). Breastfeeding may continue during treatment with zuclopenthixol decanoate if clinically indicated, but medical monitoring of the infant is recommended, especially during the first four weeks after birth.

Fertility

Cases of hyperprolactinemia, galactorrhea, amenorrhea, decreased libido, erectile dysfunction, and absence of ejaculation have been reported (see section "Adverse reactions"). These conditions may negatively affect sexual function and fertility in both women and men.

If possible, the dose should be reduced or the drug discontinued if clinically significant hyperprolactinemia, galactorrhea, amenorrhea, or sexual dysfunction develops. These disorders are reversible upon discontinuation of the drug.

Administration of zuclopenthixol to male and female rats was associated with delayed mating. In one experiment where zuclopenthixol was administered with food, impaired mating performance and reduced fertility were observed.

Effect on ability to drive or operate machinery.

Clopixol Depot is a sedative agent. Patients receiving psychotropic medications or after alcohol consumption may experience reduced attention and concentration. They should be warned about the potential impact of the drug on their ability to drive or operate machinery.

Patients should not drive if they experience blurred vision.

Method of Administration and Dosage

Adults

The dosage of the drug and the interval between injections are determined individually according to the patient's condition, aiming to achieve maximum suppression of psychotic symptoms with minimal adverse effects.

For maintenance therapy, the usual dosage range is 200–400 mg (1–2 mL) every 2–4 weeks.

Some patients may require higher doses or shorter intervals between injections. Injections exceeding 2 mL in volume should be divided and administered at two separate sites.

If the volume exceeds 2–3 mL of a 200 mg/mL solution, a more concentrated solution should be preferred.

When switching from oral zuclopenthixol or zuclopenthixol acetate to maintenance therapy with zuclopenthixol decanoate, the following guidelines should be followed.

1. Switching from oral zuclopenthixol to zuclopenthixol decanoate.

Oral daily dose (mg) ×8 = dose of zuclopenthixol decanoate (mg) every 2 weeks.
Oral daily dose (mg) ×16 = dose of zuclopenthixol decanoate (mg) every 4 weeks.

Patients should continue to take oral zuclopenthixol during the first week after the first injection, but at a reduced dose.

2. Switching from zuclopenthixol acetate to zuclopenthixol decanoate.

Simultaneously with the last injection of zuclopenthixol acetate (100 mg), administer zuclopenthixol decanoate intramuscularly at 200–400 mg (1–2 mL). Subsequent injections of zuclopenthixol decanoate should be given every 2 weeks. Higher doses or shorter intervals between injections may be prescribed if necessary.

Zuclopenthixol acetate and zuclopenthixol decanoate can be mixed in the same syringe and administered as a single injection (combined injection).

When switching from other depot formulations to 200 mg of zuclopenthixol decanoate, equivalent ratios should be considered based on 25 mg of fluphenazine decanoate, 40 mg of cis(Z)-flupenthixol decanoate, or 50 mg of haloperidol decanoate.

Dosages of zuclopenthixol decanoate and injection intervals should be adjusted according to the patient's response.

Elderly Patients. Lower therapeutic doses should be prescribed.

Renal Impairment. The drug should be administered at usual doses in patients with renal impairment.

Hepatic Impairment. Dose titration should be cautious, and, if possible, serum drug concentration monitoring is recommended.

Clopixol Depot should be administered intramuscularly into the upper outer quadrant of the buttock. Injection volumes exceeding 2 mL should be divided and administered at two separate sites. Local tolerance is good.

Children.

Use in children and adolescents is not recommended due to lack of clinical data.

Overdose.

Due to the pharmaceutical formulation, overdose is unlikely.

Symptoms: drowsiness, coma, extrapyramidal disorders, seizures, arterial hypotension, shock, hypo- or hyperthermia.

When overdose occurs concurrently with agents capable of affecting cardiac function, cases of ECG changes, QT prolongation, torsades de pointes, ventricular arrhythmias, and cardiac arrest have been reported.

Treatment

Symptomatic and supportive. Measures should be taken to maintain respiratory and cardiovascular function. Epinephrine should not be used, as it may further lower blood pressure. Seizures can be treated with diazepam, and movement disorder symptoms with biperiden.

Adverse reactions

Undesirable effects are in most cases dose-dependent. Their frequency and severity are more pronounced at the beginning of therapy and decrease during continued treatment.

Extrapyramidal disorders may develop, particularly during the first few days after injection and in the initial phase of treatment. In most cases, these can be managed by reducing the dosage and/or using anti-parkinsonian agents. Routine prophylactic use of the latter is not recommended. Anti-parkinsonian agents do not alleviate tardive dyskinesia and may even exacerbate it. It is recommended to reduce the dose or, if possible, discontinue treatment with zuclopenthixol. In cases of persistent akathisia, treatment with a benzodiazepine or propranolol is recommended.

The frequency of the adverse reactions listed below in the table is defined as:

very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), or unknown.

Cardiac disorders	Common	Tachycardia, palpitations.
	Uncommon	Prolongation of QT interval on ECG.
Blood and lymphatic system disorders	Uncommon	Thrombocytopenia, neutropenia, leukopenia, agranulocytosis.
Nervous system disorders	Very common	Somnolence, akathisia, hyperkinesia, hypokinesia.
	Common	Tremor, dystonia, hypertonia, dizziness, headache, paresthesia, attention disorders, amnesia, gait disturbance.
	Uncommon	Delayed dyskinesia, hyperreflexia, dyskinesia, parkinsonism, syncope, ataxia, speech disorders, hypotonia, seizures, migraine.
	Very rare	Malignant neuroleptic syndrome.
Visual disturbances	Common	Accommodation disorder, vision blurred.
	Uncommon	Nystagmus, mydriasis.
Ear and labyrinth disorders	Common	Dizziness.
	Uncommon	Hypersensitivity to sound, tinnitus.
Respiratory, thoracic and mediastinal disorders	Common	Nasal congestion, dyspnea.
Gastrointestinal disorders	Very common	Dry mouth.
	Common	Increased salivation, constipation, vomiting, dyspepsia, diarrhea.
	Uncommon	Abdominal pain, nausea, flatulence.
Renal and urinary disorders	Common	Urinary disorders, urinary retention, polyuria.
Skin and subcutaneous tissue disorders	Common	Hyperhidrosis, pruritus.
	Uncommon	Rash, photosensitivity reactions, pigmentation disorders, seborrhea, dermatitis, purpura.
Musculoskeletal disorders	Common	Myalgia.
	Uncommon	Muscle rigidity, trismus, torticollis.
Endocrine disorders	Uncommon	Hyperprolactinemia.
Metabolism and nutrition disorders	Common	Increased appetite, weight gain.
	Uncommon	Decreased appetite, weight loss.
	Uncommon	Hypoglycemia, impaired glucose tolerance, hyperlipidemia.
Vascular disorders	Uncommon	Arterial hypotension, flushing.
	Very rare	Thromboembolism.
General disorders and administration site conditions	Common	Asthenia, fatigue, malaise, pain.
	Uncommon	Thirst, injection site reaction, hypothermia, pyrexia.
Immune system disorders	Uncommon	Hypersensitivity, anaphylactic reaction.
Hepatobiliary disorders	Uncommon	Abnormal liver function tests.
	Very rare	Cholestatic hepatitis, jaundice.
Reproductive system and breast disorders	Uncommon	Absence of ejaculation, erectile dysfunction, orgasmic disorders in women, vaginal dryness.
	Uncommon	Gynecomastia, galactorrhea, amenorrhea, priapism.
Psychiatric disorders	Common	Insomnia, depression, anxiety, nervousness, nightmares, decreased libido.
	Uncommon	Apathy, night terrors, increased libido, confusion.
Pregnancy, puerperium and perinatal period	Not known	Withdrawal syndrome in newborns.

There have been reports of rare cases of QT prolongation, ventricular arrhythmias: ventricular fibrillation, ventricular tachycardia, cardiac arrest, torsade de pointes, and sudden death associated with the use of medicinal products belonging to the therapeutic class of antipsychotics, including zuclopenthixol decanoate.

Sudden discontinuation of zuclopenthixol decanoate may lead to withdrawal symptoms, the most common of which are nausea, vomiting, anorexia, diarrhea, rhinorrhea, sweating, myalgia, paraesthesia, insomnia, restlessness, anxiety, and agitation. Patients may also experience dizziness, fluctuating sensations of heat or cold, and tremor. Symptoms usually occur within 1–4 days after discontinuation and subside within 7–14 days.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Store in the original packaging to protect from light. Keep out of reach of children.

Incompatibilities.

Zuclopenthixol decanoate should only be mixed with zuclopenthixol acetate, which is also dissolved in medium-chain triglycerides (European Pharmacopoeia).

Zuclopenthixol decanoate must not be mixed with depot formulations containing sesame oil, as their combination alters the pharmacokinetic properties of these agents.

Packaging. 10 ampoules of 1 ml in a cardboard box.

Prescription status. Prescription only.

Manufacturer. H. Lundbeck A/S.

Manufacturer's address.
Ottiliavej 9, 2500 Valby, Denmark.